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Obesity and Depression

August 25, 2011


"I have heard that obesity can be 'depressogenic.' Is there any evidence that it can also be an obstacle to treatment?"

Vladmir Maletic, MD:

The short answer to both questions is: most likely yes! Epidemiological studies have observed that middle-aged women with greater body mass index (BMI) also have greater prevalence of depression. Simon et al 1  noted that prevalence of depression in women with normal BMI (<25) compared to an obese group (BMI>35) rose from 6.5% to 25.9%. The relationship appeared to be bidirectional; the prevalence of obesity increased from 25.4% in women with no depressive symptoms to 57.8% in women with moderate to severe depression! Not surprisingly, depression was associated with a higher daily caloric intake. This finding was recently replicated in a large national epidemiological sample: adults with abdominal obesity compared to individuals without abdominal obesity were 156% more likely to suffer from moderate-to-severe depressive symptoms (odds ratio: 2.56; confidence interval: 1.34-4.90). 2

Now that we have recognized this reciprocal relationship between depression and obesity, we will attempt to answer a more difficult question: why? Adipose tissue has a significant role as an endocrine and immune organ. 3,4  Hypothalamic-pituitary-adrenal (HPA) axis is dysregulated in both obesity and major depressive disorder (MDD); treatments for both conditions have a significant impact on HPA activity. It is not clear if the cortisol elevation in obese individuals is attributable to a more rapid turnover, decreased cortisol-binding globulin, or some other factor. Aberrant HPA activity is also a cardinal feature of MDD. Both of these conditions tend to be associated with "stress eating." 3

A recent imaging study has provided us with a unique window into the possible relationship between our food choices and mood. Sad emotion was induced in a group of healthy volunteers by visual or musical cues. Sadness was associated with a greater sensation of hunger and relieved by fatty acid, but not with saline infusion! Furthermore, fatty acid infusion was associated with a change in fMRI signal in brain stem, hypothalamus, hippocampus, and anterior-, mid-, and posterior cingulate cortices - areas that have a known role in stress response and mood regulation. 5

Accumulation of lipids in the white abdominal adipose tissue triggers the adipocyte release of inflammatory cytokines, such as interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), and chemokines (substances attracting leukocytes into fatty tissue). These pro-inflammatory compounds are known to mediate the association between obesity and cardiovascular disease, metabolic disorders (including type 2 diabetes), and even malignancy. 4  Peripheral elevation of pro-inflammatory cytokines not only accompanies MDD, chronic pain, and sleep disorders, 6  it may have an active role in shaping some of the depressive symptomatology, such as sadness, guilt, impaired concentration, fatigue, and even suicidal ideation! 7  Thus, maladaptive immune activation may be a common feature linking MDD with obesity, metabolic disorders, and cardiovascular disease.

A seminal study by Miller et a l8  supports this conclusion. After accounting for potential confounding variables such as subclinical viral infections and smoking, it was obesity that explained the major portion of association between depression and inflammation. Greater waist circumference, but not other features of metabolic syndrome, was highly predictive of developing depression in older individuals participating in a recent epidemiological study. 9  Once developed, metabolic syndrome was associated with almost threefold increase in the risk of chronicity of MDD, leading the authors to conclude that "metabolic depression" may be a chronic subtype of this disease. Finally, Kloiber at al10 described a "dose-response" relationship between an antidepressant response and BMI. Depressed patients with higher BMI (=25) showed not only a slower and less robust clinical response to antidepressant treatment, but also less improvement in attention and neuroendocrine indicators relative to patients with normal weight (BMI<25).

It appears that MDD and obesity share several pathophysiological mechanisms that explain their reciprocal relationship (the role of adipokines was discussed in detail in a previous  Q&A  by Dr. Draud). Awareness of these processes provides an opportunity for enhanced treatment approaches through dietary counseling, exercise, and monitoring of metabolic and inflammatory parameters in depressed patients.

–Vladimir Maletic, MD



  1. Simon GE, Ludman EJ, Linde JA et al.  Association between obesity and depression in middle-aged women.  Gen Hosp Psychiatry.  2008;30(1):32-39
  2. Zhao G, Ford ES, Li C et al.  Waist circumference, abdominal obesity, and depression among overweight and obese U.S. adults: National Health and Nutrition Examination Survey 2005-2006.  BMC Psychiatry.  2011;11(1):130.
  3. Bornstein SR, Schuppenies A, Wong ML, Licinio J.  Approaching the shared biology of obesity and depression: the stress axis as the locus of gene-environment interactions. Mol Psychiatry.  2006;11(10):892-902.
  4. Shelton RC, Miller AH.  Eating ourselves to death (and despair): the contribution of adiposity and inflammation to depression.  Prog Neurobiol.  2010;91(4):275-299.
  5. Van Oudenhove L, McKie S, Lassman D, et al.  Fatty acid-induced gut-brain signaling attenuates neural and behavioral effects of sad emotion in humans.  J Clin Invest. 2011;121(8):3094-3099.
  6. Maletic V, Raison CL.  Neurobiology of depression, fibromyalgia and neuropathic pain. Front Biosci.  2009;14:5291-5338.
  7. Alesci S, Martinez PE, Kelkar S et al.  Major depression is associated with significant diurnal elevations in plasma interleukin-6 levels, a shift of its circadian rhythm, and loss of physiological complexity in its secretion: clinical implications.  J Clin Endocrinol Metab.  2005;90(5):2522-2530.
  8. Miller GE, Stetler CA, Carney RM et al.  Clinical depression and inflammatory risk markers for coronary heart disease.  Am J Cardiol.  2002;90(12):1279-1283.
  9. Vogelzangs N, Beekman AT, Boelhouwer IG et al.  Metabolic depression: a chronic depressive subtype? Findings from the InCHIANTI study of older persons.  J Clin Psychiatry.  2011;72(5):598-604.
  10. Kloiber S, Ising M, Reppermund S et al.  Overweight and obesity affect treatment response in major depression.  Biol Psychiatry.  2007;62(4):321-326.
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